Development of therapeutic compounds for slit diaphragm formation by elucidating dynamics of Nephrin protein using human iPS-derived kidney organoids

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08707
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kumamoto University
• Principal Investigator: Tanigawa Shusnuke 熊本大学, 発生医学研究所, 講師 (10726318)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 病態再現 / iPS細胞 / 腎臓オルガノイド / ネフリン / 糸球体 / スリット膜 / ネフロン

Outline of Final Research Achievements

The kidney is composed of nephrons (glomeruli and renal tubules), the minimal functional units, and collecting ducts located downstream of nephrons. NEPHRIN is a trans-membrane protein that constitutes the filtration slits of the glomerulus, and its mutation causes congenital nephrotic syndrome, which is characterized by urinary leakage of blood proteins.
To elucidate the mechanisms that control the dynamics of NEPHRIN to form slit diaphragm, we utilized our original kidney organoid technology that can reproduce the structure of nephron and slit diaphragm formation of the kidney. In this study, we identified several candidate compounds that facilitate membrane localization of NEPHRIN in human iPS-derived kidney organoids.

Free Research Field

腎臓発生学

Academic Significance and Societal Importance of the Research Achievements

本計画では、ヒトiPS細胞由来腎臓オルガノイドを用いたネフリンの膜局在化を促進する化合物の同定を目的として実施し、いくつかの候補化合物を得た。申請者は本研究期間にヒトiPS由来ネフロン前駆細胞の増幅方法も報告しており(Tanigawa et al., Stem Cell Reports, 2019)、理論上、増幅した患者由来のオルガノイドを用いたスクリーニング系の確立が可能である。今後、変異ネフリンタンパク質の人為的制御が可能になると先天性疾患のみならず、濾過膜の傷害が関与すると考えられている糖尿病性腎症等他の慢性腎臓病などの糸球体の濾過機能が減衰した腎疾患に対する創薬にも発展が期待できる。